Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. This can be a reactive and benign, such as in wound healing, or result in a pathological state leading to further complications. In response to injury, fibrosis is called scarring and if fibrosis arises from a single cell line it is called a fibroma. Physiologically the process of fibrosis involves deposit of connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing.
Proliferative vitreoretinopathy (PVR) is one example of an excessive fibrotic condition which occurs in the eye. PVR is a scarring process that develops as a complication associated with primary retinal detachment (RD) and perforating ocular trauma and it is the most common cause of surgical failure upon RD treatment (Ho et al., Br J Ophthalmol 1985, 69:584-587). PVR is a dynamic process characterized by the formation of fibrotic tissue on the retina, leading to complicated retinal detachment, preventing the reattachment of the detached retina and finally may cause blindness (Lambert et al., Seminars in ophthalmology 1995, 10:49-52). Retinal pigment epithelial (RPE) cells, which compose the external cell layer of the retina, are the most critical contributors to the development of the fibrotic response of PVR. During PVR, RPE cells undergo transformation into fibroblast-like cells through a process known as the epithelial-mesenchymal transition (EMT) (Takahashi et al., J Biol Chem 2010, 285:4060-4073). In the process of converting from epithelial into mesenchymal cells, they lose their epithelial characteristics such as polarity and specialized cell-to-cell contact, and acquire migratory mesenchymal properties (Grisanti et al., Invest Ophthalmol Vis Sci 1995, 36:391-405). These processes are mediated by the expression of cell surface molecules, cytoskeletal reorganization, and extracellular matrix (ECM) components (Thiery et al., Cell 2009, 139:871-890; Kalluri et al., J Clin Invest 2009, 119:1420-1428). EMT can be triggered by different signaling molecules such as epidermal growth factor (EGF) and fibroblast growth factor (FGF), however transforming growth factor beta-1 (TGF-β1) is considered the main regulator of EMT (Garweg et al., Sury Ophthalmol 2013, 58:321-329; Lamouille et al., I 2007, 178:437-451; Charteris, Br J Ophthalmol 1995, 79:953-960).
Similar to PVR, liver fibrosis is not an independent disease but rather a histological change caused by liver damage and inflammation. Liver damage causes hepatic stellate cells (HSC) to be over active and triggers increased ECM synthesis. As a result, greater than normal amounts of collagen fiber deposits accumulate in the extra-cellular spaces of the liver cells. The collagen deposits result in loss of blood infusion and cellular hardening. Liver fibrosis is the net result of the imbalance between the collagen fiber synthesis and decomposition. When fiber synthesis is very active and decomposition is suppressed, fibrosis will progress. Conversely, fibrosis can be reversed if inflammation and collagen synthesis is controlled.
Cirrhosis always develops from fibrosis. Although fibrosis and cirrhosis are distinguishable conditions, they are closely related. At the fibrosis stage, the amount of collagen increases and the ratio of fibro-connective tissue versus liver cellular tissue increases, but the liver lobular structures remain intact, and there is no pseudo-lobule formation. Cirrhosis consists of two pathological features: fibro-connective tissue hypertrophy and pseudo-lobule formation. At the cirrhosis stage, the liver's fundamental structure is deformed, and the framework of the liver begins collapse, making reversal of condition more difficult.
TGF-β-mediated EMT, a component of fibrosis pathogenesis, has been observed in a variety of cell types, including in the eye at the lens epithelial cells, corneal epithelial cells and other. Outside of the eye, TGF-β-mediated EMT has been observed in cells as varied as epithelial cells of the colon, lung epithelial cells and in the HSC cell (Saika S, Lab Invest 2006, 86:106-115).
Hepatic fibrosis is also known to result from an imbalance in TGF-β production. TGF-β is a multifunctional cytokine with an array of biological effects such as cell growth, differentiation, immunomodulation a double-edged sword effect, oxidative stress and endoplasmic reticulum (ER) stress (Desmouliere et al., J Cell Biol 1993, 122:103-111; Yoon et al., Oncogene 2005, 24:1895-1903). Intracellular signaling downstream to the TGF-β receptor complexes is mediated by the Smads family, the canonical pathway (Zhang et al., Cell Res 2009, 19:128-139). Recent reports have demonstrated that transforming growth factor β activated kinase 1 (TAK1), a member of the mitogen-activating protein (MAP) kinase kinase kinase family, is involved in the TGF-β signaling in the non-canonical pathway (Mu Y et al., Cell Tissue Res 2011, 347:11-20; Yamaguchi et al., Science 1995, 270:2008-2011; Kajino et al., J Biol Chem 2007, 282:9475-9481). But to date, the roles of TAK1 in RPE cell signaling and mediating PVR development were unknown. TAK1 is a serine/threonine kinase that is rapidly activated by TGF-β1 and subsequently activates other MAP kinases such as p38 (Ma et al., Am J Physiol Renal Physiol 2011, 300:F1410-1421; Wang et al., J Biol Chem 1997, 272:22771-22775). Moreover, studies indicate that TAK1 can regulate TGF-β-induced activation of Smad signaling by inducing Smad7 expression and also interfering with R-Smad transactivation by direct interaction with the MH2 domain of Smad proteins (Brown et al., J Cell Biochem 2007, 101:9-33). In addition to the role of TAK1 in the regulation of Smad function, there is cross-talk between the Smad and downstream targets of TAK1 such as p38 MAPK and ATF2 in the regulation of certain TGF-β1 target gene expression (Zhang et al., Cell Res 2009, 19:128-139; Mu Y et al., Cell Tissue Res 2011, 347:11-20). Even though TAK1 activation is associated with TGF-β1 signaling, it is well known that its activation can also be caused by various stimuli including: environmental stress, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 and lipopolysaccharides (LPS) (Conner et al., Biochem J 2006, 399:427-434). Activated TAK1 can transduce signals to several downstream signaling cascades, including the MKK4/7-JNK, MKK3/6-p38 MAPK, and Nuclear Factor-kappa B (NF-kB)-inducing kinase (NIK)-IkB kinase (IKK) (Hanada et al., J Biol Chem 2001, 276:5753-5759).
Currently available surgical options for the treatment of RD are pneumatic retinopexy, scleral buckling and pars plana vitrectomy (PPV). Although PVR is primarily managed surgically and there is large improvement in the surgical techniques, the numbers of PVR patients has remained constant from 1988 to 2003. Possible explanation for this high rate of PVR can be explained by the inability to prevent some level of cell adhesion and the subsequent pathological changes in-spite of the surgical procedure of vitrectomy. Thus, there is a continuing need to develop therapies for PVR that will enable better treatment outcomes for RD and prevent PVR- (and other ocular fibrosis-) related blindness.
Available treatments for liver fibrosis depend upon the stage of the condition. At an early stage of collagen fiber formation, fibers can be decomposed with water or weak acid, and are known as soluble fibers. At a more advanced stage, older fibers become thick and hard, and cannot be decomposed by water or weak acids. Such fibers require collagen enzymes for their decomposition. Anti-fibrosis herbal treatments are also in use. The goal of such treatments is to suppress the HSC, enhance the activities of collagen enzymes, and promote the decomposition of the fibers, reducing ECM. However, a continuing need exists for anti-fibrosis treatments that directly target the causal mechanisms of disease pathogenesis.